tbuckley/cabot-search huggingface dataset:
Mutational landscape of low-grade serous carcinoma of the ovary.
Authors: Julian C. Schink, Ruchi Garg, Julia Andrea Elvin, Natalie Godbee, Amber Moran, Vicki Doctor, Bradford A. Tan, John H. Farley, Maurie Markman
Journal: Journal of Clinical Oncology (2022)

5578 Background: Tumor genomic profiling is a critical component of precision oncology allowing the detection of genomic alterations (GA) that are potential therapeutic targets. We present an analysis of comprehensive genomic profiling (CGP) of a large series of low grade serous ovarian carcinoma patients assayed in a nationwide cancer network. Methods: 40 Pts with advanced low grade serous ovarian carcinoma (LGSOC) underwent hybrid-capture based CGP for up to 324 cancer-related genes on archival tumor tissue or 62 genes on circulating tumor DNA ordered during clinical care for treatment decision-making between 01-2013 thru 06-2021. Clinically relevant genomic alterations (CRGA) were defined as associated with targeted therapies or mechanism-driven clinical trials. The treatment histories for these patients were obtained with IRB-approved retrospective review. Results: Median age was 44 years (range, 25-65), 68% were White and 23% were Black. Genomic alterations (GA) were identified in 80% (32/40) of LGSOC, of which 22 (55%) had a clinically relevant genomic alteration (CRGA). There were no apparent racial differences between mutation frequencies. The table below details the frequency of the most common of these clinically relevant mutations. Additionally, 1 patient had an ESR1 activating mutation commonly seen in acquired hormone therapy resistance in breast cancer; and single cases of the following mutations were also noted: TSC1, PTCH1, PTEN, FGFR1, and AKT2. Conclusions: In a large series of Low Grade Serous Ovarian Cancer patients assayed with CGP, 55% of pts had mutations potentially targeted by precision medicine therapy. The most common target is KRAS, seen in 33% of patients, these are potentially treatable with FAK and MEK inhibitors. Another 10% of patients had either a BRCA or ATM mutations making PARP inhibitor therapy an additional targeted treatment option. While mutations in the RAS pathway are most common in LGSOC they are not the only actionable target. Furthermore, this approach might also help identify baseline or acquired resistance to the hormone therapies often used to treat this cancer. The results of this study demonstrate the significant heterogeneity of genomic alterations in this rare cancer and highlight the importance of genomic profiling in this cancer which has a marked propensity for recurrence. [Table: see text]
Differential outcome of females with uterine versus extra-uterine leiomyosarcomas, a retrospective analysis.
Authors: Caroline Hana, Olufunke Akinbobuyi, Ashna Wadhawan, Shenae Samuels, Atif Mahmoud Hussein
Journal: Journal of Clinical Oncology (2022)

e23557 Background: Leiomyosarcomas, are aggressive sarcomas with survival rates among the lowest of all soft tissue sarcomas. Patients with uterine leiomyosarcoma (ULMS) have worse overall survival (OS) than those with extra-uterine leiomyosarcoma (EULMS). The effect of several clinical factors on OS have been investigated, including age, tumor size, grade, stage, and use of chemotherapy. Looking at the epigenetics of the 2 diseases, differentially methylated regions (DMRs) were statistically significant between the 2 groups. Methods: The 2004-2016 National Cancer Database was queried for females with ULMS and EULMS. We investigated several factors as predictors of binary survival status (alive or dead): patient’s age, race, year at diagnosis, tumor grade, size and stage, receipt of surgical treatment, chemotherapy, palliative care, surgical margins and time to treatment in days. Univariate and backward stepwise multivariate logistic regression models were used to determine prognostic factors associated with survival in each group. Kaplan-Meier (KM) method with log-rank test was used to compare OS rates between the 2 groups. All analyses were conducted using Stata/SE 15.1. Results: The total number of subjects was 16883. The median OS was 36.7 months in ULMS vs 57.2 in EULMS (P &lt; 0.001). Older age was associated with a lower likelihood of survival in both groups (OR = 0.95, P = 0.018 in ULMS; OR = 0.97, P &lt; 0.001 in EULMS). Lymphovascular invasion and receipt of palliative care were associated with a relatively large decrease in survival in ULMS only (OR = 0.25, P &lt; 0.001; OR = 0.13, P = 0.015 respectively). In the EULMS group, increased likelihood of survival was associated with later years of diagnosis (OR = 1.27; P &lt; 0.001). Larger tumor size (OR = 0.39; P = 0.001), stages II-IV or unstageable disease (OR = 0.56; P &lt; 0.001), positive surgical margins or margins that were unevaluable (OR = 0.87; P = 0.009) and receipt of systemic therapy (OR = 0.85; P = 0.016) were associated with a lower likelihood of survival. Conclusions: Our study reiterated that females with ULMS had worse OS than those with EULMS. this difference can be attributed to certain clinical risk factors, however, it may also be secondary to genetic and epigenetic factors. Surprisingly, the use of palliative care in this study was associated with poorer OS in the EULMS group. Further studies are needed to investigate the genetic map of these diseases and highlight certain potentially targetable prognostic and predictive factors. Study limitations: Our study did not stratify ULMS and EULMS according to the stage to examine if the aforementioned factors would still be relevant in the limited versus metastatic setting.
[<sup>68</sup>Ga]Ga-PSMA-11 PET baseline imaging as a prognostic tool for clinical outcomes to [<sup>177</sup>Lu]Lu-PSMA-617 in patients with mCRPC: A VISION substudy.
Authors: Phillip Kuo, Jacob Hesterman, Kambiz Rahbar, Ayse T. Kendi, Xiao X. Wei, Bruno Fang, Nabil Adra, Andrew J. Armstrong, Rohan Garje, Jeff M. Michalski, Samson Ghebremariam, Marcia Brackman, Connie Wong, Taylor Benson, Nicholas J. Vogelzang
Journal: Journal of Clinical Oncology (2022)

5002 Background: In the phase 3 VISION study, gallium ( 68 Ga) gozetotide ( 68 Ga-PSMA-11) PET/CT imaging was used to determine eligibility for lutetium ( 177 Lu) vipivotide tetraxetan ( 177 Lu-PSMA-617). Given that 177 Lu-PSMA-617 targets PSMA, we assessed the association between quantitative PSMA imaging parameters and treatment outcomes. Methods: In VISION, adults with mCRPC with ≥ 1 PSMA-positive (+) and no PSMA-negative lesions meeting the exclusion criteria were enrolled. In this sub-study, the association between imaging data from pre-enrollment 68 Ga-PSMA-11 PET/CT scans of pts in the 177 Lu-PSMA-617 group and clinical outcomes was assessed. Imaging data meeting quality requirements were analyzed for 548/551 pts. PSMA expression was quantified by 5 PET parameters: PSMA+ lesions by region, mean standardized uptake value (SUV mean ), maximum SUV (SUV max ), PSMA+ tumor volume, and tumor load (PSMA+ tumor volume × SUV mean ). Parameters were extracted from the whole body and 4 regions. Association between PET parameters and radiographic progression-free survival (rPFS; primary objective), overall survival (OS), objective response rate (ORR), and prostate–specific antigen 50 (PSA50) response was assessed. Results: Most pts (92.7%) had PSMA uptake in bone. In both the whole-body and regional analyses, statistically significant associations of PSMA PET parameters to clinical outcomes were observed (whole-body data shown in Table). Higher whole-body SUV mean was associated with improved clinical outcomes; pts in the highest quartile (SUV mean : rPFS, ≥ 10.2; OS, ≥ 9.9) had a median rPFS and OS of 14.1 and 21.4 months, vs 5.8 and 14.5 months for those in the lowest quartile (&lt; 6.0; &lt; 5.7), respectively. Absence of PSMA+ lesions in bone, liver, and lymph node, and lower PSMA+ tumor load, were indicators of good prognosis. Conclusions: Higher SUV mean is strongly associated with improved outcomes with 177 Lu-PSMA-617; clinical efficacy for different SUV levels vs the SoC arm is being assessed. Data support use of 68 Ga-PSMA-11 PET/CT scan to identify pts who will benefit from PSMA-targeted radioligand therapy.[Table: see text]
Insights into mutational differences between upper tract urothelial carcinoma and urothelial carcinoma of the bladder.
Authors: Yuanlei Chen, Zeyi Lu, Fangqin Wang, Yijie Luo, Liwei Xu
Journal: Journal of Clinical Oncology (2022)

e15125 Background: Upper tract urothelial carcinoma (UTUC) is histologically similar to bladder urothelial carcinoma (BUC), yet several clinical, biological and molecular features are unique to UTUC. UTUC may have unique genomic factors compared to BUC, while major knowledge gaps remain in our understanding of the biology and genomic landscape of UTUC. Methods: We retrospectively sequenced tumor samples and matched germline DNA using targeted next-generation sequencing methods and analyzed at least 642 cancer-associated genes. The cohort included 35 UTUC patients and 36 BUC patients. Results: Among all cases, KMT2D and TP53 were the most common mutations (account for 66% and 75% in UTUC and BUC, respectively). The most frequently mutated genes in UTUC were KMT2D (37%), TP53 (29%), ELF3 (26%), FGFR3 (23%), ASXL1 (20%), DKN2A (20%), DKN2B (17%), REBBP (17%), MT3B (17%), GNAS (17%) and PIK3CA (17%). The most frequently mutated genes in BUC were KMT2D (36%), TP53 (39%), MUC17 (14%), ARID1A (22%), GNAS (19%), RB1 (19%), BCL6 (19%), E2F3 (19%), EIF4A2 (19%) and FGF3 (19%). However significant differences in the prevalence of mutations in individual genes were observed. FGFR3 (23% vs. 8%) and ELF3 (26% vs. 11%) were more frequently altered, whereas RB1 (6% vs. 19%), E2F3 (3% vs. 19%) and BCL6 (3% vs. 19%) were less frequently altered in UTUC (P &lt; 0.05). FGFR3 mutations have been shown to be oncogenic and RB1 inactivation has been associated with genomic instability in urothelial cancer in previous researches, which represent potential therapeutic targets. Conclusions: Â UTUC and UCB exhibit significant differences in the prevalence of genomic landscape and carcinogenesis. A comprehensive understanding of the biology of UTUC and UCB is needed to identify new drug targets in order to improve clinical outcomes.
Bevacizumab in first-line chemotherapy to improve the survival outcome for advanced ovarian clear cell carcinoma: A multicenter, retrospective analysis.
Authors: Toshiyuki Seki, Shinichi Tate, Kyoko Nishikimi, Yoichi Unno, Mizue Itoi, Sadatomo Ikeda, Nobuhisa Yoshikawa, Hidehiko Akashi, Eitaro Suzuki, Naotake Tanaka, Takashi Hirakawa, Hiroaki Kajiyama, Hirokuni Takano, Kosuke Yoshihara, Aikou Okamoto, Makio Shozu
Journal: Journal of Clinical Oncology (2022)

5502 Background: Advanced ovarian clear cell carcinoma (ACCC, stage III/IV disease) is a rare tumor characterized by chemoresistance. Bevacizumab (Bev) was approved in November 2013 in Japan and became incorporated in the treatment of advanced ovarian cancer. However, the efficacy of Bev against ACCC remain unknown. We investigated the survival outcomes for ACCC, following first-line chemotherapy with or without Bev. Methods: Patients diagnosed with ACCC at seven institutions between 2008 and 2018 were enrolled in this study. Patients underwent cytoreductive surgery and taxane-carboplatin chemotherapy (78: triweekly regimen; 30: weekly regimen; 25: dose-dense regimen; 12: others) with or without concurrent and maintenance Bev (15 mg/kg/3 weeks). We compared the progression-free survival (PFS) and overall survival (OS) before (group A, n = 102) and after (group B, n = 43) Bev approval, using Kaplan–Meier method and Cox regression model. We excluded patients with poor performance status (PS) in group A, and patients who did not receive Bev due to poor PS or thrombosis in group B. Results: There was no significant difference between two groups in terms of age (p = 0.135) and initial CA125 level (p = 0.674). Thirteen (13%) and 11 (26%) patients had stage IV disease (p = 0.058) and 2 (3%) and 7 (16%) patients were of poor PS (PS ≥2) (p = 0.004) in group A and B, respectively (p = 0.058). More patients (29/43, 67%) in group B were achieved complete resection than in A group (52/102, 51%) (p = 0.068). The median cycle of Bev in B group was 16 (interquartile range: 6-21). The median follow-up time was 36 months. The median PFS increased from 12.5months in A group to 29.7 months in B group (log-rank test: p = 0.023, Wilcoxon test: p = 0.006). The median OS increased from 34.7 months in A group to 51.4 months in B group (log-rank test: p = 0.085, Wilcoxon test: p = 0.027). Multivariate analysis revealed that Bev use (Hazard ratio (HR): 0.54, p = 0.011; HR: 0.54, p = 0.019), PS &lt;2 (HR: 0.33, p = 0.013; HR: 0.29, p = 0.006) and completeness of resection (HR: 0.38, p &lt; 0.001; HR: 0.37, p &lt;0.001) were independent prognostic factors for PFS and OS. Conclusions: Incorporating Bev in first-line chemotherapy may improve PFS in patients with ACCC. [Table: see text]
Evaluation of trends in breast cancer–related content on TikTok.
Authors: Nanda Siva, Monika Koirala, Rahul Raiker, Shanawar Waris, Haig Pakhchanian, Yana Puckett
Journal: Journal of Clinical Oncology (2022)

11046 Background: Social media plays an important role in disseminating information to patients. It is important to investigate the healthcare content on popular platforms to understand the material consumed by patients that may influence their medical decision making. TikTok has over 1 billion monthly active subscribers and has become common ground to communicate healthcare information, including that of breast cancer. This study aims to provide an analysis of breast-cancer related information on TikTok. Methods: The most popular TikTok hashtag related to breast cancer was identified, and the top videos were gathered on January 23, 2022. Data was collected to reach a target of 100 videos. Exclusion criteria were non-English videos, repeated videos, or upload of movie/tv clip without educational info. The video source was characterized based on healthcare role, gender, and race. Healthcare provider was defined as an individual with a professional medical degree (MD, PA, RN, other). The videos were categorized into patient experience, educational, advertisement, and other. Specific content components, including chemotherapy, surgical intervention, mammogram, and self-breast exam, were tracked. Results: The hashtag “#breastcancer” was identified as the most popular, with 773.8 million views. The videos had a combined 258,886,300 views, 31,573,400 likes, 413,604 shares, and 567,520 comments. Of the 100 videos analyzed, 91 were uploaded by a layperson, 2 by a healthcare professional, and 7 by a company. The healthcare professionals consisted of one OB/GYN and one general surgeon. The racial designations of the main subjects in the videos were 87.2% White, 3.2% Black, 2.1% Hispanic, 4.3% Asian, and 3.2% undetermined. Content categorization revealed 81% patient experience, 22% educational, 6% advertisement, and 8% other. The major topics presented in the videos related to surgical treatment (39%), chemotherapy (37%), and radiation treatment (2%). Conclusions: An overwhelming majority of breast cancer related information on TikTok was not presented by qualified healthcare professionals and exhibited a lack of cultural diversity and inclusivity.[Table: see text]
Modeling analysis of COVID 19-related delays in colorectal cancer screening on simulated clinical outcomes.
Authors: Lesley-Ann Miller-Wilson, Vahab Vahdat, Durado Brooks, Paul J. Limburg
Journal: Journal of Clinical Oncology (2022)

e13631 Background: Colorectal cancer (CRC) screening disruptions have been observed with the COVID-19 pandemic, putting patients at risk for more advanced-stage disease at the time of diagnosis. We estimated the impact of increased use of stool-based tests for screening during the COVID-19 pandemic on near-term clinical outcomes in a simulated United States (US) population. Methods: A previously developed budget impact model was adapted to assess the impact of increasing use of multi-target stool DNA [mt-sDNA] or fecal immunochemical [FIT] tests to offset the COVID-19 related disruption in colonoscopy screening. Adults, ages 50 – 75 years, at average risk for CRC were included over a 3-year time horizon (2020 – 2023) to explore the impact of increased screening for CRC using mt-sDNA or FIT, from the perspective of a US payer. Compared to the base case (S0; 85% colonoscopy and 15% non-invasive tests), the estimated number of missed CRCs and advanced adenomas (AAs) were determined for four COVID-19-affected screening scenarios: S1, 9 months of CRC screening at 50% capacity, followed by 21 months at 75% capacity; S2, S1 followed by increasing stool-based testing by an average of 10% over 3-years; S3, 18 months of CRC screening at 50% capacity, followed by 12 months of 75% capacity; and S4, S3 followed by increasing stool-based testing by an average of 13% over 3-years. Results: Increasing the proportional use of mt-sDNA, the detection of AAs improved by 6.0% (Scenario 2 versus 1) to 8.4% (Scenario 4 versus 3) and the number of missed CRCs decreased by 15.1% to 17.3% respectively. Increasing FIT utilization improved the detection of AAs by 3.3% (Scenario 2 versus 1) to 4.6% (Scenario 4 versus 3) and the number of missed CRCs decreased by 12.9% (Scenario 2 versus 1) to 14.9% (Scenario 4 versus 3). Across all scenarios, the number of AAs detected was higher for mt-sDNA than for FIT, and the number of missed CRCs was lower for mt-sDNA than for FIT. Conclusions: Using home-based stool tests for average-risk CRC screening can mitigate the consequences of reduced colonoscopy screening resulting from the COVID-19 pandemic. Use of mt-sDNA led to fewer missed CRCs and more AAs detected, compared to FIT.
The adjudication rates between readers in Blinded Independent Central Review (BICR) of advanced esophageal cancer trials with or without immune checkpoint initiators as first-line therapy.
Authors: Yan Liu, Yi Wang, Antoine Iannessi
Journal: Journal of Clinical Oncology (2022)

4039 Background: It is challenging to use RECIST 1.1 for the response assessment in esophageal cancer, because it excludes certain examines such as the use of barium meal and endoscopy. In some esophageal trials, the study protocols also recommend not selecting the primary tumor as a target lesion, because esophageal lesion could be infiltrative in a cavity organ and difficult to measure reliable especially after treatment. Moreover, it can even be more difficult for independent central readers, as they are often blinded to patient clinical symptoms and outcomes. The aim of this study is to analyze a pool of advanced esophageal cancer trials which used RECIST 1.1, and to document the proportion of reader discrepancies, reader performance through monitoring procedures, and to provide suggestions for the reduction of read inconsistency. This study provides benchmarks of reader adjudication rate in novel esophageal cancer therapeutic trials with or without immune checkpoint inhibitors, which will help to trigger corrective actions, such as reader initial training and follow up re-training. Methods: We analyzed 4 esophageal cancer BICR trials that included 1,875 patients (8,501 time-points) involving 14 radiologists. We analyzed the adjudication rate of each trial as well as testing inter-trial differences. The analysis of adjudication allowed to compute trial and reader adjudication rate, readers endorsement rate, root causes of adjudications. Results: Trials had an average adjudication rate of 45.28% [42.60%-47.99%], while readers endorsement rates ranged [23.1%-81.6%]. The differences of target lesion selection (34.4%) and lesion measurement (40.3%) are the two main reasons that led to discordance per adjudicators’ assessment. The difference of new lesion determination and identification of non-target lesion progression contributed 17.8% and 7.5% of the discordance reasons, respectively. Conclusions: We provided benchmark performances for monitoring reader performance in trials with double reads. The discordances of baseline lesion selection and lesion measurement in follow up visits are the main reasons triggering adjudications in esophageal cancer central reading. Appropriate reader training and monitoring are solutions which can not only mitigate a large portion of the commonly encountered reading errors and help to reach more consensus on lesion selection and measurement between readers.
Whose mitochondria are more stable, male or female ones? Response of neurosteroid status of mitochondria of cerebral cortex cells to melanoma development in presense of chronic pain.
Authors: Irina V. Neskubina, Elena M. Frantsiyants, Irina V. Kaplieva, Alla I. Shikhlyarova, Ekaterina I. Surikova, Natalia D. Cheryarina, Valeria A. Bandovkina, Yulia A. Pogorelova, Ludmila P. Kuchkina, Aleksandr V. Snezhko, Dmitry A. Rozenko, Tatiana V. Ausheva, Oleg I. Kit
Journal: Journal of Clinical Oncology (2022)

e21559 Background: Gender differences in brain physiology and gender differences in pathology are usually recognized, but often are disregarded in clinical and experimental studies, resulting in numerous inaccuracies in data interpretation. The purpose of this study was to analyze levels of neurosteroid hormones in mitochondria of the cerebral cortex cells in C57BL/6 mice with subcutaneous B16/F10 melanoma growing in presence of chronic neurogenic pain (CNP). Methods: The study included male and female C57BL/6 mice (n = 336) aged 8 weeks initially weighing 21-22 g. Experimental groups were: intact animals; controls with a CNP model created by bilateral sciatic nerve ligation; comparison group 3 weeks after subcutaneous inoculation of 0.5 ml suspension of B16/F10 melanoma cells diluted 1:10; main group 3 weeks after subcutaneous melanoma growth in presence of CNP (CNP+B16/F10). Levels of estradiol (pg/g protein), estrone (pg/g protein) (DBC, Canada); progesterone (ng/g protein), total and free testosterone (pg/g protein) (XEMA, Russia) were measured in mitochondrial samples by ELISA (Tecan Infinite F50 analyzer, Austria). Results: Levels of estradiol in intact females were 3.1 times higher than in males, while estrone, progesterone, total and free testosterone were lower by 6.4, 2.7, 2.0 and 2.5 times, respectively. Only in females with CNP estradiol decreased by 3.4 times, compared to intact values, and estrone increased by 1.7 times (p&lt;0.05), testosterone by 3.9 times. Estradiol in animals with B16/F10 decreased compared with intact values by 3.1 times in females and by 1.5 times in males (p&lt;0.05). Females with B16/F10 showed the highest levels of progesterone exceeding intact values by 3.1 times. In the group with CNP+B16/F10, females showed lower levels of estradiol and estrone (by 1.4 times, p&lt;0.05) and free testosterone (by 1.6 times, p&lt;0.05), compared to the levels in CNP; on the opposite, males had 1.5 times (p&lt;0.05) higher estrone and 2.9 times lower progesterone. Conclusions: Low levels of estradiol involved in the protective mechanism of neurosteroids were the dominant factor in mitochondria of cerebral cortex cells in females with CNP and malignant neoplasms. Males did not demonstrate such dominant factor. In animals with CNP+B16/F10, the response nature of cerebral cortex mitochondria changed: all defense mechanisms in the brain of females were suppressed by the 3rd week of tumor development in presence of pain. In males, mitochondria of cerebral cortex cells were more resistant to the influence of two pathologies, and only few changes in the neurosteroid status were recorded.